Tissue growth and tumorigenesis in Drosophila: cell polarity and the Hippo pathway

2017 ◽  
Vol 48 ◽  
pp. 1-9 ◽  
Author(s):  
Helena E Richardson ◽  
Marta Portela
Keyword(s):  
Cell Polarity ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Drosophila Cell ◽  
The Hippo Pathway

scholarly journals The palmitoyltransferase Approximated promotes growth via the Hippo pathway by palmitoylation of Fat

2016 ◽  
Vol 216 (1) ◽  
pp. 265-277 ◽  
Author(s):  
Hitoshi Matakatsu ◽  
Seth S. Blair ◽  
Richard G. Fehon
Keyword(s):  
Posttranslational Modification ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Negative Regulator ◽  
Pathway Activity ◽  
Protein Association ◽  
Junctional Region ◽  
Growth Loss ◽  
The Hippo Pathway

The large protocadherin Fat functions to promote Hippo pathway activity in restricting tissue growth. Loss of Fat leads to accumulation of the atypical myosin Dachs at the apical junctional region, which in turn promotes growth by inhibiting Warts. We previously identified Approximated (App), a DHHC domain palmitoyltransferase, as a negative regulator of Fat signaling in growth control. We show here that App promotes growth by palmitoylating the intracellular domain of Fat, and that palmitoylation negatively regulates Fat function. Independently, App also recruits Dachs to the apical junctional region through protein–protein association, thereby stimulating Dachs’s activity in promoting growth. Further, we show that palmitoylation by App functions antagonistically to phosphorylation by Discs-overgrown, which activates Fat. Together, these findings suggest a model in which App promotes Dachs activity by simultaneously repressing Fat via posttranslational modification and recruiting Dachs to the apical junctional region, thereby promoting tissue growth.

scholarly journals Want to promote tissue growth? There’s an App for that!

2016 ◽  
Vol 216 (1) ◽  
pp. 1-1 ◽  
Author(s):  
Ben Short
Keyword(s):  
Hippo Pathway ◽  
Tissue Growth ◽  
The Hippo Pathway

Study describes how a palmitoyltransferase regulates the Hippo pathway in flies.

scholarly journals Differential regulation of the Hippo pathway by adherens junctions and apical–basal cell polarity modules

2015 ◽  
Vol 112 (6) ◽  
pp. 1785-1790 ◽  
Author(s):  
Chih-Chao Yang ◽  
Hillary K. Graves ◽  
Ivan M. Moya ◽  
Chunyao Tao ◽  
Fisun Hamaratoglu ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Basal Cell ◽  
Mammalian Cells ◽  
Adherens Junctions ◽  
Hippo Pathway ◽  
Tumor Formation ◽  
Nuclear Accumulation ◽  
Binding Motif ◽  
Downstream Effectors ◽  
The Hippo Pathway

Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical–basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non–cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non–cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.

scholarly journals Yorkie-independent negative feedback couples Hippo pathway activation with Kibra degradation

2020 ◽  
Author(s):  
Sherzod A. Tokamov ◽  
Ting Su ◽  
Anne Ullyot ◽  
Richard G. Fehon
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
The Core ◽  
Pathway Activation ◽  
The Hippo Pathway ◽  
Transcriptional Output

AbstractThe Hippo signaling pathway regulates tissue growth in many animals. Multiple upstream components are known to promote Hippo pathway activity, but the organization of these different inputs, the degree of crosstalk between them, and whether they are regulated in a distinct manner is not well understood. Kibra activates the Hippo pathway by recruiting the core Hippo kinase cassette to the apical cortex. Here we show that the Hippo pathway downregulates Kibra levels independently of Yorkie-mediated transcriptional output. We find that the Hippo pathway promotes Kibra degradation via SCFSlimb-mediated ubiquitination, that this effect requires the core kinases Hippo and Warts, and that this mechanism functions independently of other upstream Hippo pathway activators including Crumbs and Expanded. Moreover, Kibra degradation appears patterned across tissue. We propose that Kibra degradation by the Hippo pathway serves as a negative feedback loop to tightly control Kibra-mediated Hippo pathway activation and ensure optimally scaled and patterned tissue growth.

scholarly journals Genome-Wide Screen for Context-Dependent Tumor Suppressors Identified Using in Vivo Models for Neoplasia in Drosophila

2020 ◽  
Vol 10 (9) ◽  
pp. 2999-3008 ◽  
Author(s):  
Casper Groth ◽  
Pooja Vaid ◽  
Aditi Khatpe ◽  
Nelchi Prashali ◽  
Avantika Ahiya ◽  
...  
Keyword(s):  
Large Scale ◽  
Hippo Pathway ◽  
Growth Control ◽  
Growth Factor Receptor ◽  
Tissue Growth ◽  
In Vivo Models ◽  
Genome Wide ◽  
Positive Regulators ◽  
The Hippo Pathway

Abstract Genetic approaches in Drosophila have successfully identified many genes involved in regulation of growth control as well as genetic interactions relevant to the initiation and progression of cancer in vivo. Here, we report on large-scale RNAi-based screens to identify potential tumor suppressor genes that interact with known cancer-drivers: the Epidermal Growth Factor Receptor and the Hippo pathway transcriptional cofactor Yorkie. These screens were designed to identify genes whose depletion drove tissue expressing EGFR or Yki from a state of benign overgrowth into neoplastic transformation in vivo. We also report on an independent screen aimed to identify genes whose depletion suppressed formation of neoplastic tumors in an existing EGFR-dependent neoplasia model. Many of the positives identified here are known to be functional in growth control pathways. We also find a number of novel connections to Yki and EGFR driven tissue growth, mostly unique to one of the two. Thus, resources provided here would be useful to all researchers who study negative regulators of growth during development and cancer in the context of activated EGFR and/or Yki and positive regulators of growth in the context of activated EGFR. Resources reported here are available freely for anyone to use.

scholarly journals The Hippo Pathway: Biology and Pathophysiology

2019 ◽  
Vol 88 (1) ◽  
pp. 577-604 ◽  
Author(s):  
Shenghong Ma ◽  
Zhipeng Meng ◽  
Rui Chen ◽  
Kun-Liang Guan
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Size Control ◽  
Tissue Growth ◽  
Cell Contact ◽  
Energy Status ◽  
Downstream Effectors ◽  
Kinase Cascade ◽  
Fate Decision ◽  
The Hippo Pathway

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1/2 and LATS1/2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell–cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein–coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases.

scholarly journals SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sung Jun Bae ◽  
Lisheng Ni ◽  
Adam Osinski ◽  
Diana R Tomchick ◽  
Chad A Brautigam ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Activation Loop ◽  
Hippo Signaling ◽  
Ww Domains ◽  
Kinase Activation ◽  
Genetic Ablation ◽  
Kinase Cascade ◽  
The Hippo Pathway

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.

scholarly journals Ack promotes tissue growth via phosphorylation and suppression of the Hippo pathway component Expanded

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Lianxin Hu ◽  
Jiajun Xu ◽  
Meng-Xin Yin ◽  
Liguo Zhang ◽  
Yi Lu ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Tissue Growth ◽  
The Hippo Pathway

Phospho-regulation of KIBRA by CDK1 and CDC14 phosphatase controls cell-cycle progression

2012 ◽  
Vol 447 (1) ◽  
pp. 93-102 ◽  
Author(s):  
Ming Ji ◽  
Shuping Yang ◽  
Yuanhong Chen ◽  
Ling Xiao ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Memory Performance ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Cycle Progression ◽  
Mitotic Kinases ◽  
The Hippo Pathway

KIBRA (kidney- and brain-expressed protein) is a novel regulator of the Hippo pathway, which controls tissue growth and tumorigenesis by regulating both cell proliferation and apoptosis. In mammals, KIBRA is associated with memory performance. The physiological function and regulation of KIBRA in non-neuronal cells remain largely unclear. We reported recently that KIBRA is phosphorylated by the mitotic kinases Aurora-A and -B. In the present study, we have expanded our analysis of KIBRA's role in cell-cycle progression. We show that KIBRA is also phosphorylated by CDK1 (cyclin-dependent kinase 1) in response to spindle damage stress. We have identified KIBRA Ser542 and Ser931 as main phosphorylation sites for CDK1 both in vitro and in vivo. Moreover, we found that the CDC (cell division cycle) 14A/B phosphatases associate with KIBRA, and CDK1-non-phosphorylatable KIBRA has greatly reduced interaction with CDC14B. CDC14A/B dephosphorylate CDK1-phosphorylated KIBRA in vitro and in cells. By using inducible-expression cell lines, we show further that phospho-regulation of KIBRA by CDK1 and CDC14 is involved in mitotic exit under spindle stress. Our results reveal a new mechanism through which KIBRA regulates cell-cycle progression.

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